RESUMO Objetivo: Relatar os casos de duas pacientes com doença inflamatória intestinal de início muito precoce (em inglês VEOIBD) secundária a mutações do receptor de interleucina 10 (IL-10R), explorar dados de imunofenotipagem e perfil de citocinas plasmáticas nesses casos em comparação com indivíduos saudáveis e descrever o fenótipo de mutações IL-10/IL-10R com base em uma revisão da literatura. Descrição do caso: Duas lactentes do sexo feminino foram encaminhadas ao nosso centro terciário, ambas com dez meses no momento do encaminhamento, com doença colônica e perianal grave, bem como desnutrição significativa, tendo uma resposta limitada aos agentes de terapia usuais de doença inflamatória intestinal (DII). No primeiro caso, o sequenciamento completo do exoma revelou mutação homozigótica (c. 537G>A/p.T179T) no exon 4 do gene IL-10RA, enquanto no segundo caso heterozigosidade composta foi identificada também no gene IL-10RA [chr11: 117.859.199 - variante A>G/p.Tyr57Cys e chr11: 117.860.335 - variante G>T/ p.Val123Leu]. Ambas as pacientes foram submetidas a Transplante de Células-Tronco Hematopoiéticas. A investigação imunológica das pacientes revelou aumento dos níveis plasmáticos de IL-10 e aumento da IgA. Comentários: Nossos relatos de casos descrevem novos achados no perfil de citocinas plasmáticas na deficiência de IL-10R, e relatamos o fenótipo grave da deficiência de IL-10/IL-10R que deve ser reconhecido pelos médicos.

ABSTRACT Objective: To report two patients with very-early-onset inflammatory bowel disease (VEOIBD) secondary to interleukin-10 receptor (IL-10R) mutations, explore immunophenotyping data and plasma cytokine profile on these cases compared to healthy controls, and describe the phenotype of IL-10/IL-10R mutations based on a literature review. Case description: We report on two female infants referred to our tertiary center at the age of ten months, with severe colonic and perianal disease, as well as significant malnutrition, who had shown limited response to usual inflammatory bowel disease (IBD) therapy agents. In the first case, whole-exome sequencing (WES) revealed a homozygous (c.537G>A/p.T179T) mutation in exon 4 of the IL-10RA gene, while in the second patient, compound heterozygosity was identified, also in the IL-10RA gene (chr11:117.859.199 variant A>G/p.Tyr57Cys and chr11: 117.860.335 variant G>T/p.Val123Leu). Both patients underwent hematopoietic cell transplantation (HCT). Immunological work-up of these patients revealed increased IL-10 plasma levels and increased IgA. Comments: Our case reports disclose novel findings on plasma cytokine profile in IL-10R deficiency, and we describe the severe phenotype of IL-10/IL-10R deficiency that should be recognized by physicians.

Abstract Objective: This minireview gathers the scientific foundations of the literature on genetic errors in the development of the humoral immune system to help pediatricians suspect these defects. Sources: A systemic search using the PubMed MEDLINE database was performed for all Predominantly Antibody Deficiencies (PADs) described in the 2020 IUIS Expert Committee for PID classification system, combined with terms for hypogammaglobulinemia. Search terms for PADs were based on the listed names and affected genes as classified by the IUIS 2020. Abstracts of the results were reviewed to find relevant case series, review articles of PADs associated with infection, opportunistic infection, autoimmunity, cytopenias, malignancies, inflammatory diseases, neurological and respiratory diseases. References from relevant articles were further reviewed for additional references. Relevant findings were grouped in accordance with the IUIS 2020 classification system. Clinical and genetic features, if known, were described. Data synthesis: PADs refer to impaired antibody production due to molecular defects intrinsic to B cells or a failure of interaction between B and T cells. The patients develop recurrent or chronic infection or respond to the antigens with dysregulation of the immune function, causing severe allergy, autoimmunity, inflammation, lymphoproliferation and malignancy. The diagnosis is a combined exercise of clinical and laboratory investigation similar to that performed by Bruton (1952). In the context of SARS-CoV-2 infection, the experience of XLA and CVID patients has been surprising. Variants in 39 genes were reported as causing PADs, but the clinical heterogeneity within each variant is not clear. Conclusion: Bruton (1952) used clinical expertise and protein electrophoresis to identify XLA. The IUIS (2020) committee used immunoglobulins and B lymphocyte to characterize PADs. Pediatricians should suspect it to detect it and prevent morbidities that can have an astonishing and irreversible impact on the child's life.

Background: Crohn's disease (CD) is a chronic transmural inflammation of the gastrointestinal tract of unknown cause. Malnutrition associated with active CD has been reduced although obesity has increased. Dietary strategies such as those with high-protein have been proposed to reduce body fat. This study compares the effects of two supplements on the nutritional status of CD patients. Materials and Methods: 68 CD patients were randomized in two groups: whey protein group (WP) and soy protein group (SP). Using bioimpedance analysis, anthropometry and albumin and pre-albumin dosages the nutritional status was measured before starting the intervention and after 8 and 16 weeks. The disease activity was determined by Crohn's Disease Activity Index and serum C-reactive protein dosage and dietary intake by 24h dietary recalls. Results: Forty-one patients concluded the study and both supplements changed body composition similarly. Triceps skin fold thickness (p< 0.001) and body fat percentage (p=0.001) decreased, whereas mid-arm muscle circumference (p=0.004), corrected arm muscle area (p=0.005) and body lean percentage (p=0.001) increased. Conclusions: For Crohn's disease patients undergoing anti TNF-alpha and azatioprine therapies, supplementation with whey and soy proteins changes body composition through reduction of body fat and thus contributes to control inflammation.

Introducción: La enfermedad de Crohn (EC) es un trastorno inflamatorio crónico transmural del tracto gastrointestinal de carácter desconocida. La desnutrición asociada con EC activa se ha reducido a pesar de la obesidad que ha aumentado. Se han propuesto estrategias dietéticas, como aquellos con alto contenido de proteínas para reducir la grasa corporal. Este estudio compara los efectos de dos suplementos sobre el estado nutricional de los pacientes con EC. Materiales y Métodos: Fueron randomizados en dos grupos 68 pacientes con EC: el grupo de proteína de suero y el grupo de proteína de soya. Se utilizo el análisis de bioimpedancia eléctrica, la antropometría y dosificaciones de albúmina y prealbúmina del estado nutricional midiéndose antes de comenzar la intervención y después de 8 y 16 semanas. La actividad de la enfermedad se determinó por Índice de Actividad de Enfermedad de Crohn (CDAI), dosificación en suero de la proteína C reactiva y la ingesta dietética por recordatorio de 24h. Resultados: Cuarenta y un pacientes concluyeron el estudio y ambos suplementos cambiaron la composición corporal de manera similar. El espesor del pliegue cutáneo del tríceps (p <0,001) y el porcentaje de grasa corporal (p = 0,001) se redujeron, mientras que la circunferencia muscular braquial (p = 0,004), el área muscular del brazo corregida (p = 0,005) y el porcentaje corporal magra (p = 0,001) han aumentado. Conclusiones: En los pacientes con enfermedad de Crohn sometidos con anti-TNF-alfa y terapias azatioprina, la suplementación con proteínas de suero de leche y de soya cambia la composición corporal a través de la reducción de la grasa corporal y por lo tanto contribuye para controlar la inflamación.

Kocuria roseabelongs to genus Kocuria(Micrococcaceaefamily, suborder Micrococcineae, order Actinomycetales) that includes about 11 species of bacteria. Usually, Kocuria spare commensal organisms that colonize oropharynx, skin and mucous membrane; Kocuria spinfections have been described in the last decade commonly affecting immunocompromised patients, using intravenous catheter or peritoneal dialysis. These patients had mainly bacteremia/recurrent sepsis. We hereby describe the case of a 10-year-old girl, immunocompetent, who had endocarditis/sepsis by K. roseawhich was identified in five different blood cultures by Vitek2 ID-GPC card (BioMérieux, France). Negative HIV serology, blood count within normal range of leukocytes/neutrophils and lymphocytes, normal fractions of the complement, normal level of immunoglobulins for the age; lymphocyte immunophenotyping was also within the expected values. Thymus image was normal at chest MRI. No catheters were required. Identification of K. roseawas essential to this case, allowing the differentiation of coagulase-negative staphylococci and use of an effective antibiotic treatment. Careful labo- ratory analysis of Gram-positive blood-born infections may reveal more cases of Kocuria spinfections in immunocompetent patients, which may collaborate for a better understanding, prevention and early treatment of these infections in pediatrics.

INTRODUCTION: Adherence, which is crucial to the success of antiretroviral therapy (HAART), is currently a major challenge in the care of children and adolescents living with HIV/AIDS. OBJECTIVE: To evaluate the prevalence of nonadherence to HAART using complementary instruments in a cohort of children and adolescents with HIV/AIDS followed in a reference service in Campinas, Brazil. METHODS: The level of adherence of 108 patients and caregivers was evaluated by an adapted standardized questionnaire and pharmacy dispensing records (PDR). Non-adherence was defined as a drug intake lower than 95% (on 24-hour or seven-day questionnaires), or as an interval of 38 days or more for pharmacy refills. The association between adherence and clinical, immunological, virological, and psychosocial characteristics was assessed by multivariate analysis. RESULTS: Non-adherence prevalence varied from 11.1% (non-adherent in three instruments), 15.8% (24-hour self-report), 27.8% (seven-day self-report), 45.4% (PDR), and 56.3% (at least one of the outcomes). 24-hour and seven-day self-reports, when compared to PDR, showed low sensitivity (29% and 43%, respectively) but high specificity (95% and 85%, respectively). In multivariate analysis, medication intolerance, difficulty of administration by caregiver, HAART intake by the patient, lower socioeconomical class, lack of virological control, missed appointments in the past six months, and lack of religious practice by caregiver were significantly associated with non-adherence. CONCLUSION: A high prevalence of HAART non-adherence was observed in the study population, and PDR was the most sensitive of the tested instruments. The instruments employed were complementary in the identification of non-adherence.

OBJETIVOS: Avaliar as características do sono de adolescentes infectados pelo HIV e estudar se os aspectos psicossociais estão associados à qualidade do sono. MÉTODOS: Estudo transversal, que avaliou 102 adolescentes, com idades entre 10 e 20 anos, infectados pelo HIV, e 120 controles, de ambos os gêneros. Para a coleta de dados, aplicaram-se: a Sleep Disturbance Scale for Children, a Epworth Sleepiness Scale, e o Pediatric Quality of Life Inventory. RESULTADOS: Verificou-se prevalência de distúrbios do sono em 77,4% dos pacientes e em 75% nos controles, e houve correlação entre qualidade do sono e de vida. Adolescentes HIV-positivos apresentaram maior pontuação nos distúrbios respiratórios do sono e maior prevalência de sonolência diurna excessiva. CONCLUSÕES: Adolescentes infectados pelo HIV apresentaram qualidade de sono semelhante à da população saudável. Isso provavelmente decorre pela melhora de suas condições de vida resultante do sucesso da terapia antirretroviral em pacientes HIV-positivos e pelas vulnerabilidades que afetam adolescentes brasileiros de grandes centros urbanos.

OBJECTIVES: To assess sleep characteristics of adolescents infected by HIV, and to ascertain whether psychosocial aspects are associated to the quality of sleep. METHODS: A cross-sectional study assessing 102 HIV-infected adolescents of both genders, aged between 10 and 20 years-old and 120 Controls. Data collection was performed by applying the Sleep Disturbance Scale for Children, the Epworth Sleepiness Scale, and the Pediatric Quality of Life Inventory. RESULTS: A sleep disturbance prevalence of 77.4% was found in patients, and a 75% prevalence in controls, and there was correlation between quality of sleep and of life. HIV-infected adolescents scored higher for sleep breathing disorders and had higher prevalence of excessive daytime sleepiness. CONCLUSIONS: HIV-infected adolescents had similar quality of sleep compared to healthy adolescents. This may be explained by the steady improvements in daily living as a result of successful anti-retroviral therapy, and by the vulnerability that affects Brazilian adolescents living in major urban centers.

Amostras de proteínas de soro de leite bovino (S-1 a S-5) foram testadas, in vivo e in vitro, para algumas propriedades nutricionais e bioatividades. Para os testes in vivo foram usados ratos da linhagem Wistar alimentados por 21 dias com dieta AIN-93G modificada quanto ao teor de proteína (12 g proteínas.100 g-1 de dieta). Os parâmetros nutricionais medidos não diferiram entre as proteínas do soro de leite administradas através das dietas. O teor de glutationa nos eritrócitos foi mais elevado para o grupo alimentado com a amostra S-3. No grupo alimentado com S-3, a secreção de citocinas (IL-10 e TNF-α) por células humanas mononucleares da circulação periférica, cultivadas no meio RPMI-1640, foi mais elevada na ausência do antígeno BCG do que em sua presença. A secreção de IL-4 foi inibida em todos os tratamentos. O IC50, concentração de proteína de soro necessária para inibir 50% da proliferação de células de melanoma de camundongo foi 2,68 mg.mL-1 de meio de cultura para a amostra S-3 e 3,66 mg.mL-1 para a amostra S-2. Com base nesses resultados concluiu-se que a amostra S-3 (concentrado de proteína de soro enriquecida com TGF-β e lactoferrina) produziu melhores respostas nutricional e imunológica quando comparada aos demais produtos testados.

Whey protein samples (S-1 to S-5) were tested in vivo and in vitro for nutritional properties and selected bioactivities. Weanling male Wistar rats fed modified AIN-93G (12 g protein.100 g-1) diets for 21 days were used the in vivo studies. The nutritional parameters did not differ among the protein diets tested. Erythrocyte glutathione content was considered high and was higher for S-3, but liver glutathione was the same for all dietary groups. For S-3, cytokine secretion (IL-10 and TNF-α) by human peripheral blood mononuclear cells (in RPMI-1640 medium) was higher in the absence of antigen than in the presence of BCG antigen. Interleukin-4 secretion was repressed in all treatments. The IC50, whey protein concentration required to inhibit 50% of the melanoma cell proliferation, was 2.68 mg.mL-1 of culture medium for the S-3 sample and 3.66 mg.mL-1 for the S-2 sample. Based on these results, it was concluded that S-3 (whey protein concentrate enriched with TGF-β and lactoferrin) produced better nutritional and immunological responses than the other products tested.

CONTEXTO E OBJETIVO: Reações adversas a drogas são um problema significativo em pacientes sob terapia antiretroviral (TARV). Determinamos a freqüência de valores elevados de enzimas hepáticas em um grupo de crianças e adolescentes infectados pelo HIV sob TARV e os fatores de risco associados. TIPO DE ESTUDO E LOCAL: Estudo transversal, realizado na Divisão de Imunodeficiência em Pediatria, Hospital das Clínicas, Universidade Estadual de Campinas. MÉTODOS: Foram analisados prontuários médicos de 152 crianças e adolescentes (54,6% masculino) infectados pelo HIV sob TARV, com dosagens de enzimas hepáticas, em média, 2,6 exames por paciente. A mediana de idade foi 7,48 anos. Clinicamente os pacientes foram classificados nas categorias N (6), A (29), B (78) e C (39). Foram avaliados os níveis séricos de aspartato aminotransferase e alanina aminotransferase. O sistema de escore da hepatotoxicidade foi: grau 1 (1,1 a 4,9 x• limite superior ao normal, i.e., LSN), grau 2 (5,0 - 9,9 x LSN), grau 3 (10,0 - 15,0 x •LSN) e grau 4 (>15,0 x •LSN). Para determinar os fatores de risco de hepatotoxicidade, foram avaliados odds ratio (OR) e odds ratio ajustado (aOR) para idade, gênero, contagem de linfócitos TCD4+ e uso de medicações. RESULTADOS: Observamos hepatotoxicidade grau 1 em 19,7% (30/152) pacientes. Não foi detectada hepatotoxicidade grau 2, 3 ou 4. Houve uma associação significativa entre a hepatotoxicidade e uso de sulfas (OR, 3,61; IC 95%, 1,50 -8,70; ORajustado, 3,58; IC 95%, 1,44 - 8,85) e agentes antituberculose (OR, 9,23; IC 95%, 1,60 - 53,08; ORajustado, 9,05, IC 95%, 1,48 - 55,25), mas não estava associada com TARV. CONCLUSÃO: Um quinto dos pacientes apresentaram hepatotoxicidade leve, atribuída ao uso de agentes antituberculose e sulfas. Nossos resultados sugerem que TARV foi bem tolerada.

CONTEXT AND OBJECTIVE: Adverse drug reactions are a significant problem in patients on antiretroviral therapy (ART). We determined liver enzyme elevation frequencies in HIV-infected children and adolescents receiving ART, and their association with risk factors. DESIGN AND SETTING: Cross-sectional study, at the Pediatrics Immunodeficiency Division, University Hospital, Universidade Estadual de Campinas. METHODS: Medical records of 152 children and adolescents (54.6% male; median age 7.48 years) were analyzed, with a mean of 2.6 liver enzyme determinations per patient. Clinically, patients were classified in categories N (6), A (29), B (78) and C (39). Serum levels of aspartate aminotransferase and alanine aminotransferase were evaluated. Hepatotoxicity was scored as grade 1 (1.1-4.9 times upper limit of normality, ULN), grade 2 (5.0-9.9 times ULN), grade 3 (10.0-15.0 times ULN) and grade 4 (> 15.0 times ULN). To assess hepatotoxicity risk factors, odds ratios (OR) and adjusted odds ratios (aOR) for age, gender, TCD4+ cell count, viral load and medication usage were calculated. RESULTS: We observed grade 1 hepatotoxicity in 19.7 % (30/152) patients. No cases of grade 2, 3 or 4 were detected. There was a significant association between hepatotoxicity and use of sulfonamides (OR, 3.61; 95% confidence interval (CI), 1.50-8.70; aOR, 3.58; 95% CI, 1.44-8.85) and antituberculous agents (OR, 9.23; 95% CI, 1.60-53.08; aOR, 9.05; 95% CI, 1.48-55.25). No toxicity was associated with ART. CONCLUSIONS: One fifth of patients experienced mild hepatotoxicity, attributed to antituberculous agents and sulfonamides. Our results suggest that ART was well tolerated.

CONTEXTO E OBJETIVO: A ocorrência de desnutrição é freqüente em crianças com infecção pelo HIV. O objetivo do estudo foi estudar a ocorrência de desnutrição e sua relação com a mudança de categoria clínica em crianças infectadas pelo HIV. TIPO DE ESTUDO E LOCAL: Estudo longitudinal, no Departamento de Pediatria e Centro de Investigação em Pediatria (CIPED). Faculdade de Ciências Médicas da Universidade Estadual de Campinas (Unicamp). MÉTODOS: Revisamos os prontuários de 127 pacientes com infecção perinatal pelo HIV com o propósito de obter medidas de peso e estatura no início do acompanhamento ambulatorial, no momento da mudança de categoria clínica e cinco meses após a mudança. Estes dados foram transformados em z-escores de peso/idade, altura/idade e peso/altura. Os testes de Wilcoxon, Kruskal-Wallis e o cálculo da razão de chances foram usados. RESULTADOS: 51 (40,2%) das crianças avaliadas apresentavam desnutrição, sendo 40 (31,5%) com comprometimento de altura, e portanto com maior risco de inclusão na categoria clínica C. Encontramos associação entre condição nutricional, categoria clínica e idade no início dos sintomas. 36 (28,4%) pacientes mudaram de categoria clínica durante o acompanhamento, e a mudança ocorreu em idade mais precoce entre os desnutridos. O grupo que mudou de categoria clínica manteve as mesmas distribuições de z-escore de peso, altura e peso/altura durante o acompanhamento. CONCLUSÃO: A gravidade das manifestações da aids associa-se com a condição nutricional e com a idade de início dos sintomas. A mudança de categoria clínica não se acompanhou de piora no estado nutricional.

CONTEXT AND OBJECTIVE: Malnutrition is common among HIV-infected children. Our objective was to study the occurrence of malnutrition and its relationship with changes in clinical category among HIV-infected children. DESIGN AND SETTING: Longitudinal study, at the Pediatrics Department and Pediatrics Investigation Center (CIPED), Faculdade de Ciências Médicas da Universidade Estadual de Campinas (Unicamp). METHODS: We reviewed the hospital records of 127 vertically HIV-infected children. Anthropometric measurements were obtained at the beginning of follow-up, at clinical category change and five months later. These were converted to z-scores of weight/age, height/age and weight/height. Data were presented as means, standard deviations, frequency counts and percentages. The Wilcoxon and Kruskal-Wallis tests and odds ratios were used in the analysis. RESULTS: We found that 51 (40.2%) were undernourished and 40 (31.5%) were stunted, with higher risk of being included in clinical category C. There was an association between nutritional condition and the clinical categories of the Centers for Disease Control classification (1994), and with age at symptom onset (except for height z-score). During follow-up, 36 patients (28.4%) changed their clinical category, which occurred early among the undernourished patients. The group that changed its clinical category maintained the same z-score distribution for weight, height and weight/height throughout follow-up. CONCLUSION: Aids manifestation severity was associated with nutritional status and with age at symptom onset, but change in clinical category was not followed by worsening of nutritional status.

CONTEXTO: Atualmente há estudos limitados que definem parâmetros de crescimento e estado nutricional em crianças com HIV. OBJETIVO: Estudar o estado nutricional de crianças infectadas com o vírus da imunodeficiência humana. TIPO DE ESTUDO: Estudo longitudinal. LOCAL: Serviço de imunodeficiência pediátrica da Universidade Estadual de Campinas, Campinas, Brasil. PARTICIPANTES: 124 crianças nascidas de mulheres infectadas com o HIV foram avaliadas desde o nascimento até dois anos de idade. Elas foram subdivididas em dois grupos: 71 crianças infectadas e 53 crianças não-infectadas. PROCEDIMENTOS: A avaliação do estado nutricional foi realizada pela comparação do Z-score para peso/idade(P/I),altura/idade(A/I) e peso/altura(P/A),usando as curvas do NCHS como referência. Para a comparação do Z-score foram utilizados os testes T de Student e U de Mann-Whitney. Os testes foram conduzidos ao nível de significância=5%. RESULTADOS: A análise do Z-score revelou que houve evidência de diferença entre os dois grupos, para todas as variáveis estudadas, exceto o índice de A/I aos 3 meses e P/A aos 21 meses. CONCLUSÕES: O estado nutricional das crianças infectadas foi gravemente afetado em comparação com as crianças sororreversoras no mesmo grupo de idade. Embora as manifestações clínicas possam demorar a aparecer, as alterações no crescimento surgem logo após o nascimento.

CONTEXT: There are today only a limited number of studies defining growth parameters and nutritional status for HIV children. OBJECTIVE: To study the nutritional status of infants infected with the human immunodeficiency virus. TYPE OF STUDY: Longitudinal study. SETTING: Department of Pediatrics, Faculty of Medical Sciences, UNICAMP, Campinas, Brazil. PARTICIPANTS: One hundred and twenty-four children born to HIV infected mothers were evaluated from birth until the age of two years. They were subdivided into two groups: 71 infected children and 53 non-infected children. MAIN MEASUREMENTS: Growth was evaluated in both groups by comparing Z-scores for weight/age (w/a), length/age (H/a) and weight/length (w/H) (using the NCHS curves as reference). RESULTS: The Z-score analyses showed that there was a significant difference between the two groups for all the variables studied, except for the H/a value at 3 months of age and the W/H value at 21 months of age, which showed P > 0.05. CONCLUSIONS: The growth of infected infants was observed to be severely affected in comparison with that of seroreversed infants in the same age groups. Although clinical manifestations may take time to appear, the onset of growth changes begin soon after birth.